Jue Jiang’s research while affiliated with Renji Hospital and other places

Lung injury, which is associated with systemic inflammatory responses, is a common problem with significant morbidity and mortality. Here, we examined the involvement of toll-like receptor 4 (TLR4) and nuclear factor erythroid 2-related factor 2 (Nrf2) on intestinal ischemia-reperfusion (I/R)-induced lung injury in vivo and in vitro. Analysis of lung tissues in Nrf2-knockout mice by western blotting, immunohistochemistry, and TUNEL assay, and analysis of bronchoalveolar lavage fluid showed that Nrf2 deficiency upregulated TLR4, enhanced I/R-induced lung injury, apoptosis, inflammation, and autophagy, and increased the I/R-induced inactivation of Akt. In mouse lung epithelial cells subjected to oxygen and glucose deprivation/reperfusion (OGD/Rep), Nrf2 silencing increased the OGD/Rep-induced upregulation of TLR4 and MyD88 and downregulation of HO-1, and exacerbated OGD/Rep-induced apoptosis, autophagy, and the downregulation of phospho-Akt. TLR4 silencing and Akt inhibition experiments indicated that OGD/Rep-induced cell death by suppressing Akt signaling, and Nrf2 protected lung cells by modulating TLR4 and Akt signaling. These results indicated that the Nrf2/TLR4/Akt axis plays a role in inflammation-associated lung damage, suggesting potential therapeutic targets for the treatment of lung injury.

Sevoflurane, an inhalational anesthetic, is extensively used during oral cancer surgery. However, the effect of sevoflurane on head and neck squamous cell carcinoma (HNSCC) remains unclear. The objective of the present study was to investigate the effects of sevoflurane on the proliferation, apoptosis and invasion in HNSCC cell lines and the underlying molecular mechanism. The Cell Counting Kit-8 assay was used to evaluate cell proliferation. Apoptosis was analyzed by flow cytometry. Cell invasion was evaluated using the Transwell invasion assay. The expression levels of Akt, p-Akt (Ser473), hypoxia‑inducible factor-1α (HIF-1α), Fas and Bcl-2 were measured by western blotting. Significant inhibition of cell proliferation and induction of apoptosis were observed in FaDu and CAL-27 cells following sevoflurane treatment. The expression of Akt, p-Akt (Ser473) and Bcl-2 was supressed, while that of Fas was significantly increased, which was partly associated with the activation of the HIF-1α pathway. In addition, the results revealed a statistically significant inhibition of cell invasion in the FaDu cell line following exposure to 2 and 4% sevoflurane for 2, 4, 6 and 8 h. Therefore, the present study demonstrated that sevoflurane decreased the malignant behavior of HNSCC cell lines in vitro, which was associated with activation of the HIF-1α pathway.

Sevoflurane is the most widely used anaesthetic administered by inhalation. Exposure to sevoflurane in neonatal mice can induce learning deficits and abnormal social behaviours. MicroRNA (miR)-27a-3p, a short, noncoding RNA that functions as a tumour suppressor, is upregulated after inhalation of anaesthetic, and peroxisome proliferator-activated receptor γ (PPARγ) is one of its target genes. The objective of this study was to investigate how the miR-27a-3p-PPARγ interaction affects sevoflurane-induced neurotoxicity. A luciferase reporter assay was employed to identify the interaction between miR-27a-3p and PPARγ. Primary hippocampal neuron cultures prepared from embryonic day 0 C57BL/6 mice, were treated with miR-27a-3p or a PPARγ agonist to determine the effect of miR-27a-3p and PPARγ on sevoflurane-induced cellular damage. Cellular damage was assessed by a flow cytometry assay to detect apoptotic cells, immunofluorescence to detect reactive oxygen species, western blotting to detect NOX1/4 and ELISA to measure inflammatory cytokine levels. In vivo experiments were performed using a sevoflurane-induced anaesthetic mouse model to analyse the effects of miR-27a-3p on neurotoxicity by measuring the number of apoptotic neurons using the TUNEL method, and learning and memory function by employing the Morris water maze test. Our results revealed that PPARγ expression was downregulated by miR-27a-3p following sevoflurane treatment in hippocampal neurons. Downregulation of miR-27a-3p expression decreased sevoflurane-induced hippocampal neuron apoptosis by decreasing inflammation and oxidative stress-related protein expression through the upregulation of PPARγ. In vivo tests further confirmed that inhibition of miR-27a-3p expression attenuated sevoflurane-induced neuronal apoptosis, and learning and memory impairment. Our findings suggest that downregulation of miR-27a-3p expression ameliorated sevoflurane-induced neurotoxicity and learning and memory impairment through the PPAR-γ signalling pathway. MicroRNA-27a-3p may therefore be a potential therapeutic target for preventing or treating sevoflurane-induced neurotoxicity. This article is protected by copyright. All rights reserved.

Signaling pathways of tumor necrosis factor-α (TNF-α) and insulin-like growth factor-I (IGF-I) are found to be functionally interrelated in some experimental studies. IGF-I may be involved in the pathogenesis of postoperative cognitive dysfunction (POCD). In order to investigate the possible interaction of TNF-α and IGF-I in POCD, the plasma levels of IGF-I and TNF-α were determined in 44 patients under general anesthesia. As compared with non-POCD patients, POCD patients showed increased TNF-α and decreased IGF-I levels in plasma, as well as a significant negative correlation between TNF-α and IGF-I values. The present results suggest that interaction of increased TNF-α levels and decreased IGF-1 levels might lead to a vicious circle, which may contribute to POCD.

Lipopolysaccharide (LPS) plays an important role in lung endothelial apoptosis which is crucial for lung fibrogenesis in ARDS progression. Reactive oxygen species (ROS) has been reported to be involved in LPS-induced lung epithelial cell apoptosis. Propofol is a commonly used intravenous anesthetic agent in clinic and it could attenuate LPS-induced epithelial cells oxidation and apoptosis. However, the mechanisms are still obscure. In this study, we examined whether and how propofol attenuates LPS-induced oxidation and apoptosis in BEAS-2B cells. Compared with control group, LPS up-regulated Pin-1, phosphatase A2 (PP2A) expression, induced p66Shc-Ser³⁶ phosphorylation, and facilitated p66Shc mitochondrial translocation, thus leading to superoxide anion (O2⁻) generation, mitochondrial cytochrome c release, active caspase 3 over-expression and cell viability inhibition. Importantly, propofol was shown to down-regulate LPS-induced PP2A expression, limit p66Shc mitochondrial translocation, decrease O2⁻ generation, inhibit mitochondrial cytochrome c release, reduce active caspase 3 expression, and recover cells viability, while propofol had no effects on LPS-induced Pin-1 expression and p66Shc-Ser³⁶ phosphorylation. Moreover, the protective effects of propofol on LPS-induced BEAS-2B cells apoptosis were similar to that of calyculin A, which is an inhibitor of PP2A. We also found that FTY720, which is an activator of PP2A, can effectively reverse the protective function of propofol. Our data illustrated that propofol could alleviate LPS-induced BEAS-2B cells oxidation and apoptosis through down-regulating PP2A expression, limiting p66Shc-Ser³⁶ dephosphorylation and p66Shc mitochondrial translocation, decreasing O2⁻ generation, mitochondrial cytochrome c release, activating caspase 3 expression.

Insulin-like growth factor (IGF)-1 functions as a neuroprotective hormone and may protect against cognitive impairment, which may occur as a result of sevoflurane exposure. The aim of the present study was to assess the effect of sevoflurane on the production of IGF‑1 and investigate the molecular mechanisms underlying this regulation. The BRL rat hepatocyte cell line and adult mice were exposed to 1 or 2 minimal alveolar concentrations sevoflurane for 4 or 8 h. IGF‑1 and microRNA‑98 levels were quantified using an enzyme‑linked immunosorbent assay, western blotting and reverse transcription‑quantitative polymerase chain reaction analyses. The importance of microRNA‑98 in the regulation of IGF‑1 by sevoflurane was investigated using a microRNA‑98 inhibitor. Sevoflurane treatment reduced IGF‑1 levels and simultaneously upregulated microRNA‑98 expression levelsin rat hepatocytes and adult mice. Inhibition of microRNA‑98 attenuated this effect. Therefore, sevoflurane may reduce the synthesis of IGF‑1 by upregulating microRNA‑98 expression.

Insulin-like growth factor 1 (IGF-1) is a neuroprotective hormone and a decrease in levels of circulating IGF-1 contributes toward cognitive decline. The aim of this study was to investigate the effect of sevoflurane on the level of circulating IGF-1 and cognitive function in aged mice and the role of circulating IGF-1 in the cognitive dysfunction induced by sevoflurane. Aged mice were exposed to 1 or 2 minimal alveolar concentrations of sevoflurane for 4 or 8 h. Before and after the exposure, blood was collected from the tail vein and serum IGF-1 was measured by an enzyme-linked immunosorbent assay. After exposure, spatial learning and memory were tested in the Morris water maze. An intraperitoneal injection of IGF-1 was used to study the role of IGF-1 in the cognitive impairment induced by sevoflurane. Sevoflurane dose dependently decreased the serum IGF-1 concentration, and resulted in aged mice taking significantly longer and traveling significantly further to find the platform. Sevoflurane significantly decreased the times crossing the platform and %time spent in target quadrant relative to the control group. IGF-1 attenuated this effect, but could not completely reverse it. We conclude that downregulation of circulating IGF-1 contributes toward the cognitive impairment induced by sevoflurane.

Background: Sevoflurane is an inhaled anesthetic commonly used in the pediatric. Recent animal studies suggest that early exposure to high concentration of sevoflurane for a long duration can induce neuroapoptosis and later cognitive dysfunction. However, the neurodevelopmental impact induced by lower concentration and shorter exposure duration of sevoflurane is unclear. To investigate whether early exposure to 2% concentration of sevoflurane for a short duration (clinically relevant usage of sevoflurane) can also induce neuroapoptosis and later cognitive dysfunction. Methods: Rat pups were subjected to control group, 2% sevoflurane for 3h and 3% sevoflurane for 6h. TUNEL assay and apoptotic enzyme cleaved caspase-3 measured by western blot were used for detection of neuronal apoptosis in frontal cortex and CA1 region of hippocampus 24 after sevoflurane treatment. Long-term cognitive function was evaluated by Morris water maze and passive avoidance test as the rats grew up. Results: The apoptotic levels in frontal cortex and CA1 region were significantly increased after rats exposed to 3% sevoflurane for 6h (P<0.05), but not 2% sevoflurane for 3h (P>0.05). Exposure to both 2% sevoflurane for 3h and 3% sevoflurane for 6h could cause long-term cognitive dysfunction and animals exposed to 3% sevoflurane for 6h exhibited worse neurodevelopmental outcomes (P<0.05). Conclusion: It was suggested that neuronal apoptosis might not contribute to long-term cognitive dysfunction induced by 2% concentration and short exposure time of sevoflurane. Our findings also suggested that the mechanisms of sevoflurane-induced neurodevelopmental impact might be various, depending on the concentration and exposure duration.

Insulin-like growth factor (IGF)-1 is implicated in learning and memory. Experimental studies have suggested that the IGF-1 system is beneficial in cognition, especially in Alzheimer's disease (AD), by opposing Aβ amyloid processing and hyperphosphorylated tau toxicity. Low IGF-I and insulin-like growth factor binding protein (IGFBP)-3 serum levels are significantly associated with AD. To assess the relationship between circulating IGF-I and IGFBP3 levels and change of postoperative cognition. The study was performed in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. On the day before the operation and postoperative days 1, 3 and 7, mini-mental state examination (MMSE) was performed by the same doctor, and blood samples were collected at 08:00 h after overnight fasting. The circulating levels of IGF-1 and IGFBP3 were measured by enzyme-linked immunosorbent assay. One hundred and two patients completed all four MMSE tests and forty-four of them completed all the four blood samples collection. Postoperative circulating IGF-1 level, ratio of IGF-1/IGFBP3 and MMSE score significantly decreased, whereas IGFBP3 level significantly increased compared with preoperative values in total patients. The change trends of circulating IGF-1 level and MMSE score were similar. Preoperative circulating IGF-1 level, ratio and MMSE score were significantly lower in POCD group compared to non-POCD group. There was no significant difference in preoperative level of circulating IGFBP3 between the two groups. Preoperative circulating IGF-1 level was negatively correlated with age and positively with MMSE. Logistic regression analysis revealed that lower preoperative IGF-1 level and elderly patients increased the odds of POCD. Down-regulation of circulating IGF-1 level may be involved in the mechanism of postoperative cognitive dysfunction. Older patients had lower circulating IGF-1 levels and were more susceptible to POCD.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). We previously identified tetranectin (TET) as a potential biomarker for PD whose expression is downregulated in the cerebrospinal fluid of PD patients. In the present study, we investigate the role of TET in neurodegeneration in vitro and in vivo. Our results showed that siRNA knockdown of TET decreased cell viability and the number of tyrosine hydroxylase (TH) positive cells, whereas it increased caspase-3 activity and the Bax/Bcl-2 ratio in cultured primary dopaminergic neurons. Overexpression of TET protected dopaminergic neurons against neuronal apoptosis in 1-methyl-4-phenylpyridinium cell culture model in vitro. In TET knockdown mouse model of PD, TET gene deletion decreased the number of TH positive cells in the SNpc, induced apoptosis via the p53/Bax pathway, and significantly impaired the motor behavior of transgenic mice. The findings suggest that TET plays a neuroprotective role via reducing neuron apoptosis and could be a valuable biomarker or potential therapeutic target for the treatment of patients with PD.